TY  - JOUR
AU  - Özkan, Burak
AU  - Ramge, Jan-Moritz
AU  - Wiesner, Diana
AU  - Scekic-Zahirovic, Jelena
AU  - Antonucci, Stefano
AU  - Nungeß, Sandra
AU  - Gebauer, Dorothea
AU  - Ignatius, Anita
AU  - Weishaupt, Jochen H
AU  - Haffner-Luntzer, Melanie
AU  - Roselli, Francesco
TI  - Reduced osteogenic factors and early osteoblast senescence in SOD1(G93A) ALS mouse model.
JO  - JCI insight
VL  - 11
IS  - 5
SN  - 2379-3708
CY  - Ann Arbor, Michigan
PB  - JCI Insight
M1  - DZNE-2026-00263
SP  - e197475
PY  - 2026
AB  - Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease. Emerging evidence suggests manifestations beyond the neuromuscular system. Bone alterations are part of the ALS clinical picture; it remains unclear whether they are secondary to muscle denervation or due to an autonomous process. We investigated skeletal involvement in the SOD1(G93A) mouse model at presymptomatic (P45) and symptomatic (P110) stages through biomechanical and transcriptomic approaches. Three-point bending revealed significant reductions in femoral rigidity and maximum bending force in SOD1 mutants at P45, indicating early structural deficits. Micro-CT analysis demonstrated reduced trabecular bone mineral density and thickness at P45, with progressive trabecular loss and cortical thinning by P110. Histological examination revealed marked osteoblast loss at P45, suggesting impaired bone formation as the primary early mechanism. Transcriptomics of bulk bone and cultured osteoblasts from P45 mice identified dysregulation of bone differentiation, including downregulation of osteoblast differentiation genes and upregulation of negative regulators of ossification and increased cell senescence signatures. Unfolded protein response was upregulated in SOD1 osteoblasts. Immunohistochemistry confirmed the senescence phenotype with increased p16Ink4a level in SOD1 osteoblasts. These findings suggest that bone deterioration precedes overt motor symptoms and is linked to osteoblast premature senescence.
KW  - Animals
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Amyotrophic Lateral Sclerosis: physiopathology
KW  - Osteoblasts: metabolism
KW  - Osteoblasts: pathology
KW  - Disease Models, Animal
KW  - Mice
KW  - Superoxide Dismutase-1: genetics
KW  - Superoxide Dismutase-1: metabolism
KW  - Osteogenesis: genetics
KW  - Mice, Transgenic
KW  - Cellular Senescence: genetics
KW  - X-Ray Microtomography
KW  - Bone Density
KW  - Male
KW  - Humans
KW  - Cell Differentiation
KW  - Superoxide Dismutase
KW  - Bone biology (Other)
KW  - Cell biology (Other)
KW  - Cellular senescence (Other)
KW  - Neurodegeneration (Other)
KW  - Neuroscience (Other)
KW  - Osteoclast/osteoblast biology (Other)
KW  - Superoxide Dismutase-1 (NLM Chemicals)
KW  - SOD1 G93A protein (NLM Chemicals)
KW  - Sod1 protein, mouse (NLM Chemicals)
KW  - Superoxide Dismutase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41569660
DO  - DOI:10.1172/jci.insight.197475
UR  - https://pub.dzne.de/record/285487
ER  -